Therapeutic proteins have been widely used for treatment of human diseases due to their great biocompatibility and specificity. However, their very short half-lives in vivo are problematic in developing them for clinical applications. In order to overcome the short half-life issue of therapeutic proteins, several studies have been conducted, such as shielding protein for protection, blocking renal filtration, or cellular uptake, etc. Conjugation of fatty acid, especially palmitic acid, has been used to extend the half-life of certain peptide drugs, such as insulin analogs, because fatty acid is a ligand of human serum albumin of which serum half-life is over three weeks. Albumin is known to evade intracellular degradation by binding neonatal Fc receptor (FcRn) in endosome, followed by exocytosis to the blood. Therefore, conjugation of palmitic acid to therapeutic peptides/proteins was expected to extend the serum half-life via binding to human serum albumin in the patients’ blood. Nevertheless, conjugation of palmitic acid to extend the serum half-life was limited to peptides or proteins with a low molecular weight. In our previous studies, fatty acid conjugation to urate oxidase, a gout-treating protein with a high molecular weight (135 kDa), did not extend the serum half-life. In order to address the issue, we examined the crystal structures of FcRn and human serum albumin including fatty acid binding sites, and designed the various linkers. With those linkers, we successfully extended the serum half-life of urate oxidase.

Designing fatty acid-conjugated therapeutic proteins with a high molecular weight for the extended serum half-life

2019 Spring National Meeting

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